The goal of this proposal is to better understand the role of the hypothalamus in drug addiction. While the hypothalamus is known to be important in regulating reward-related and motivated behavior such as feeding, surprisingly little is understood about its function in regulating responses to drugs of abuse. We will focus our experiments on the orexin neuropeptide, which is synthesized in neurons of the lateral hypothalamus (LH), a region previously implicated in reward-related behavior. While orexin is known to be important in regulation of sleep, the receptors for orexin are expressed in diverse brain areas that are known targets for drugs of abuse, such as the locus coeruleus and ventral tegmental area. Our data suggests that orexin plays an important role in mediating the development of physical dependence to morphine. We will explore the effects of drugs on orexin neurons and how the neuropeptides then influence target brain regions and modulate responses to drugs of abuse. We will use mutant mice, pharmacological reagents, biochemical analysis, and viral gene manipulations to answer the following questions: What is the mechanism by which orexin regulates physical dependence and withdrawal from morphine? What is the role of direct opiate action, via mu-opioid receptors, on orexin neurons? What is the importance of orexin signaling to the locus coeruleus in mediating the development of physical dependence or the expression of drug withdrawal? These studies will begin to define novel brain circuits that influence the biology of addiction. By determining the molecular and neuronal mechanisms of orexin action, we will establish a better understanding of the relationship between the hypothalamus and drugs of abuse. Moreover, these neuropeptide pathways may provide additional targets for therapeutics aimed at controlling or treating drug addiction.